Emergency room triage of patients with acute chest pain by means of rapid
testing for cardiac troponin T or troponin I

Authors

Hamm C, Goldmann B, Heeschen C, Kreymann G, Berger J, Meinertz
T.

Source

New England Journal of Medicine. 337:1648-53. December
4, 1997.

Institutions

University Hospital Eppendorf, Hamburg, Germany

Support

None indicated

Background

Myocardial injury, commonly assessed by CPK-MB levels, can be detected
with greater sensitivity by assaying blood levels of the cardiac contractile
proteins troponin T and I. These have been shown to have prognostic significance
in the setting of acute ischemic syndromes, such as unstable angina. With
the development of rapid bedside assays for these proteins, their use in
the evaluation of chest pain in the emergency room becomes feasible. This
study was designed to investigate the diagnostic and prognostic value of
rapid bedside troponin testing in emergency room patients with chest pain
and without ST-segment elevation on EKG.

Methods

Patients

Patients were eligible if they presented to the emergency room of the
University Hospital with less than 12 hours of anterior or left-sided chest
pain, not explained by trauma or obvious abnormality on chest x-ray.

Patients with ST-segment elevation or recent MI were excluded.

Protocol

Troponin assays

Blood was obtained for troponin T and I assays within 15 minutes of
arrival at the ER and again four hours later. For those patients who had
arrived less than two hours after the onset of pain, a third sample was
drawn 6 hours after the onset of pain (so that all patients had one sample
drawn at least 6 hours after the onset of pain).

A rapid, qualitative bedside assay for troponin T was performed on all
samples and the results were immediately available to the treating physicians.

Serum was centrifuged and frozen for quantitative troponin T measurement
as well as for rapid qualitative and quantitative troponin I measurements.

Other clinical data

Patients also had EKG's performed, blood drawn for CPK and MB fractions
and history and physical examination recorded according to a protocol.

After excluding patients with ST-segment elevation, the admission EKG
was classified as:

ST segment depression (with or without T-wave inversions)

T-wave inversion only

Nondiagnostic (paced or bundle branch block)

Normal

Follow-up and endpoints

MI at the time of admission was judged to be present if the CPK within
24 hours of admission was greater than twice the upper limits of normal
with an elevated MB fraction.

Patients were followed during hospitalization and for 30 days after
discharge. Endpoints were death from cardiac causes and nonfatal MI (more
than 24 hours after admission).

Results

Patients and clinical diagnoses

870 eligible patients were screened between June, 1994 and March, 1996.
There were 97 with ST-segment elevation, which left 773 study patients
with chest pain but no ST-segment elevation.

The final diagnoses were:

Acute MI (by CPK): 47 patients

Unstable angina: 315

Stable angina: 121

Heart failure: 15

Pulmonary embolus: 12

Myocarditis: 5

No specific cardiovascular diagnosis: 258

487 patients were admitted to the hospital (63%), 224 to the ICU.

Qualitative and quantitative troponin tests

There was good correspondence between the rapid bedside assays and the
quantitative assays -- 94.8% for troponin T and 98.7% for troponin I. There
was only one false negative for troponin T and 5 for troponin I.

Troponins and clinical diagnoses

Of the 773 patients, 16% had at least one positive troponin T result;
22% had at least one positive troponin I. Approximately 40% of patients
with a positive test had a negative first sample.

CPK-documented MI within the first 24 hours (47 patients):

On admission, troponin T was positive in 51%, troponin I in 66%, CPK-MB
was elevated in 53%.

Four hours later, troponin T was positive in 94%, troponin I in 100%, CPK-MB
in 91%

Unstable angina (315 patients): 22% had at least one positive troponin
T; 36% had at least one positive troponin I; 5% had elevation of CPK-MB
(presumably the total CPK did not rise enough to qualify for acute MI).

Other diagnoses:

CHF: 1 positive troponin T, 5 positive troponin I

PE: 1 positive troponin T, 2 positive troponin I

myocarditis: 1 positive troponin T, 2 positive troponin I

unexplained chest pain: 1 positive troponin I

False positives

Seven patients had an elevated troponin T but normal troponin I; these
were considered to be false positives. Six of these patients also had renal
failure.

EKG and troponins

Normal EKG was present in 331 patients (43%). At least one positive
troponin test (both T and I) was present in 10% of these. One of the 47
myocardial infarctions on admission was in this group.

Non-diagnostic EKG (paced or bundle branch block) was present in
87 patients (11%). The percentage of positive troponin T and I tests in
this group was 32% and 47%, respectively. Of the 47 myocardial infarctions,
23 were in this group.

ST-segment depression was present in 158 patients (20%). The percentage
of positive troponin T and I tests was 32% and 56%. There were 8 myocardial
infarctions in this group.

T-wave inversions only were present in 197 patients (25%). Positive
troponin T and I tests were present in 6% and 5%. There were 15 myocardial
infarctions in this group.

Troponin and events during follow-up

There were 20 deaths from cardiac causes during the follow-up
period (11 in hospital and 9 after discharge). The troponin T test was
positive in 16 out of these 20 patients; troponin I was positive in all
but one.

Myocardial infarction after admission occurred in 14 patients
(9 in hospital, 5 after discharge). Troponin T was positive in 11 and negative
in 3. Troponin I was positive in 13 and negative in 1.

For the 34 total events, troponin I was positive in 32 and negative
in 2. Troponin T was positive in 27 and negative in 7. The EKG was normal
in 5 and abnormal or nondiagnostic in 29.

In the 331 patients with a normal EKG, there were 5 events. Four of
these had an abnormal troponin T, all 5 had an abnormal troponin I.

The overall event rate for patients with negative troponin T was 1.1%,
and for negative troponin I 0.3%. Troponin T and troponin I provided additional
prognostic information, after EKG status and CPK-MB were taken into account.

Author's discussion

The authors state that "the primary aim of this study was to demonstrate
that two negative test results on admission and four hours later (or at
least six hours from the onset of chest pain) allow safe early discharge".
Patients with two normal troponin measurements had a low rate of cardiac
events within 30 days (1.1% for troponin T; 0.3% for troponin I).

They note that patients with one positive result should be admitted
and evaluated further, and that a single test on admission is not sufficient.
They feel that the slightly higher sensitivity of the troponin I test "may
be related to different release kinetics and different limits of detection
of the versions of the test that are currently available". They also feel
that the six false positives seen in patients with renal failure may reflect
a true difference between the troponin T and I assays.

Editorial

In an accompanying editorial, Dr. Mark Hlatky from Stanford University
reviews the problem of the evaluation of chest pain in the emergency room.
He makes several important points about this article:

Patients with a positive troponin test who were classified as unstable
angina could also be classified as "small myocardial infarctions".

Since no details about the clinical history were given, it is not possible
to determine the risk of events in clinically high-risk subsets with negative
troponin tests.

The results obtained here only apply when at least two samples are obtained,
with one sample at least 6 hours after the onset of chest pain.

Among patients with ST-segment depression, the event rates with negative
troponin T and I were 2.8% and 1.4%, not negligeable numbers.

Comment

This was a study of 773 patients evaluated in an emergency room for chest
pain without ST-segment evaluation. Patients underwent troponin T and I
determination; the troponin T results were immediately available and all
patients with a positive test were admitted. Patients with negative troponin
tests had a good prognosis -- the event rate (cardiac MI or death) within
30 days was 1.1% for patients with a negative troponin T test and 0.3%
for patients with a negative troponin I test.

In addition to the limitations noted in Dr. Hlatky's editorial, there
is another problem with the study that greatly limits its applicability,
in my opinion. Of the 773 patients, 487 were admitted to the hospital,
the vast majority with a diagnosis of unstable or stable angina. Overall,
123 patients had at least one positive troponin T test and 171 had a positive
troponin I test. This means that at least 364 patients were admitted to
the hospital with negative troponin T tests and at least 316 with negative
troponin I tests.

Thus, a large number of patients with negative troponin tests were admitted
to the hospital, mainly with the diagnoses of unstable and stable angina,
and presumably received treatment for this. Their good prognosis could
be in part related to in-hospital therapy (such as heparin), not only to
their negative troponin tests.

Although we can conclude that patients who are appropriately treated
(including hospitalization) have a good prognosis with negative troponins,
we cannot conclude from this study that it is safe to discharge patients
from the emergency room, even with normal EKG's and negative troponin tests,
since so many patients in this study were, in fact, hospitalized. We do
not know how they would have fared had they been discharged from the emergency
room.

The objective of this study, according to the authors, was to demonstrate
that "two negative test results on admission and four hours later (or at
least six hours from the onset of chest pain) allow safe early discharge".
This has not yet been persuasively accomplished, in my opinion.

December 20, 1997

References

Reader Comments

Date: Sun, 21 Dec 1997
From: "Mark Leber" <besterdoc@email.msn.com>

I feel that the paper contributes to improving accuracy in ruling out
cardiac chest pain in the emergency room. If serial troponin I can predict
greater than 99% of cardiac events within 30 days, then we could discharge
patients more quickly from the emergency room, especially patients who
are weak rule outs.

I agree that a prospective trial is needed to determine what combination
of tests should be done (serial cpk mbs, serial troponins and serial ekgs)
to best r/o cardiac events, since the troponin study was done in isolation
of the other modalities ordinarily used. Also, it would be interesting
to know how often troponins agreed with serial cpk mbs and ekgs.

Mark Leber,M.D.

If the troponin I test should turn out to perform with a sensitivity
of 99% for subsequent events, then it will be useful for the ER evaluation
of "soft rule-outs". I don't believe this has been proven, yet.

The troponin tests are more sensitive than CPK-MB's, and more specific
than the EKG. In multivariate analysis (table 4 in the article), troponins
did add a significant amount of prognostic information to that derived
from CPKs and from the EKG, separately and in combination. -- mj

January 11, 1998

I received the following letter from Dr. Christian Hamm, corresponding
author of this study.

Dear Dr. Jacobson,

Thank you for considering our paper on troponins for your internet journal
club.

I appreciate your comments and agree that discharge of patients based
on 2 biochemical tests requires further validation. However, you may have
overlooked that troponins are much better parameters than CK, ECG or the
clinical evaluation (see table 4). Please read our position which is clearly
stated in the discussion: "bedside tests for troponin T and troponin I
result in more accurate diagnoses than do previous more time-consuming
methods and allow safer and more rapid decision making for most
patients with acute chest pain."

I share your concerns with respect to a possible influence of hospital
admissions of troponin negative patients on the prognosis. However, there
is no evidence at all that any therapy today has influence on the inhospital
outcome even of troponin positive patients. Moreover, if you refer to table
1 you may appreciate that most events occurred after discharge in troponin
positive patients. Therefore, your point is well taken but plays very likely
no major role. The answer could only be given, if you randomize patients
with negative tests to hospitalization and discharge. In my view, this
is, however, a very unrealistic study design. Again, I like to refer to
our discussion which states: "The troponin test cannot replace the clinical
evaluation of the patient with chest pain."

I am grateful to Dr. Hamm for these clarifying comments. I agree
that this study supports the notion that troponin tests provide useful
prognostic information, over and above the EKG and traditional cardiac
enzymes.

My main concern is that negative troponin tests should not be used
to justify discharging patients from the ER who have a good history for
unstable angina. We seem to agree on this point as well.

-- mj

Date: Thu, 29 Jan 1998
From: johann steurer <polstf@usz.unizh.ch>

I don`t understand why the patients with a myocardial infarction within
24 hours after hospitalisation were excluded from the final analysis of
the results??

J.Steurer MD, Zürich
www.evimed.ch

Patients with a myocardial infarction within the first 24 hours
were excluded from analysis for the endpoint of recurrent MI only. This
makes sense, since they are not recurrent infarctions but, rather, presented
initially with an infarction. -- mj

In the April 30, 1998 New England Journal of Medicine are several
letters
to the editor about this study, two of which raise the same points
that were raised here.

Date: Wed, 10 Mar 1999
From: TOPFL54@aol.com

Dr. Jacobson,

At first I was quite skeptical about the use of troponins in determining
who can safely go home from the ER. However over the past several months
I have routinely ordered troponin I in all of my chest pain patients
and it is quite good in discriminating acute coronary syndromes from non
cardiac causes. It is always elevated in my non q wave MI' s, frequently
in my people with unstable angina with or without ecg changes (who subsequently
have coronary disease on invasive studies) and never in those who subsequently
do not have coronary disease.

I am aware that my experience is limited and anecdotal but when I combine
a negative spect technetium sestamibi and a normal troponin in a patient
with a normal or non diagnostic EKG I can comfortably send them home in
12-24 hrs with further followup. The insurance companies are rapidly putting
pressure on us to "fast track" these patients who do not have acute ischemic
syndromes and while I abhor this intrusion I dont think it will abate.
However in patients where my clinical suspicion is not high, the EKG is
not overtly ischemic and the troponins plus the spect technetium is non-ischemic
I can usually get them home if not from the ER then in 6-12 hrs from our
observation bed and feel comfortable albeit not arrogant that they will
not have a life threatening event.

John D. Vance MD

This brings up a point that applies to many, if not most,
studies: their frequent use for supporting an "agenda", in addition to
their official purpose of furthering medical knowledge. The ability
to improve our diagnostic efficiency with regard to cardiac ischemia will
certainly be used (and misused) to cut costs in the ER. -- mj

As commentary on letter by Dr Vance. There is no logic in using a one
off troponin test as back-up support to discharge a patient with non-diagnostic
EKG if the troponin is done too early. My reading of recent literature
suggests you must wait at least 6 hours from onset of pain.

I wonder if Dr Vance is drawing the troponin level at the beginning
or at the end of his period of observation.

Additionally I am seeing a number of articles in the last 12 months
that seem to indicate troponin is not superior to CK-MB, especially CK-MB
sub forms. Although we have switched to troponin at my hospital I feel
the jury is still out.

Dr Paul Cunningham FACEM
Concord Hospital, Sydney Australia

Clearly, the troponin can't be used to send home a patient
if drawn too soon after the onset of chest pain. It is easier to
perform at the bedside and may be somewhat more sensitive than the CK,
however, and thus could be used to justify admitting a patient whose story
is otherwise not very convincing. -- mj

Date: June 6, 1999
From: John Vance [jdvmd54@worldnet.att.net]

Dr. Jacobson,

In response to Dr. Cunninghams letter. First I perform a Troponin I
at least 6 hours after the onset of chest pain. Secondly I never discharge
a patient based solely on a normal troponin. They are usually in an observation
unit undergoing clinical assesment, further ekgs, serum markers and usually
a technetium sestamibi scan. They are then discharged usually in 12 hrs
if the troponins AND the nuclear scan are BOTH normal. My comments were
related to my impression that so far troponins have been an excellent predictor
of cardiac events. However I am not using a normal level to justify discharging
a patient from the ER. I do think that if a clinician combines a good history
with the ekg, serum troponins, nuclear scans and clinical judgement he/she
can safely discharge those patients with a negative workup. However if
my "gut" says otherwise I will keep them in house longer regardless of
the initial workup. Nonetheless for most of my chest pain patients with
an "atypical" history and normal or near normal ekgs the above protocol
has been very useful and so far successful.

John D. Vance MD

January 24, 2000
John Guiang [iqguiang@egis.net]

Greetings!

I have recently come across this issue of using Troponin assays to screen
patients at the ER. In our hospital, the Troponin T assay is available, however
it takes some time before the results come out. This, along with CPKs and EKGs
are all done at the ER. The parameters we use to decide whether to admit a
patient for observation or not are only the ECG and the patient's clinical
history. Convincing history seems to carry the greatest weight of all the
available diagnostics. What I mean is, we will always admit a patient with a
very clearcut history and profile even if the ECG, enzymes, and Troponins turn
out to be negative at the ER. We may not even proceed to do the assays if the
history was not convincing enough, and that's the time we send someone home from
the ER. Moroever, we also have to consider cost as another factor that carries a
lot of weight.

Isauro Q. Guiang, Jr. MD
Internal Medicine
Philippines

January 24, 2000
makeitso [makeitso@gateway.net]

While doing some research online, I came across your interesting article. My area of concern is false positive troponin I tests. In our laboratory we use two instruments for troponins, the Bayer Immuno 1 and the Abbott Axsym. Recently our pathologist and cardiologists have brought a few cases of elevated troponins
to my attention, where the other markers (ekg, ck total, ckmb and so on) don't warrant an elevated troponin. Mechanical and tech error
have been eliminated and I need to find out other causes of false positives. Both
manufacturers assure me their technology is not to blame but interfering substances and other medical factors must be affecting the assays. Any help you can offer would be appreciated.

Thank you

Bree Ann Boroff MT

I assume renal failure was not the problem. Anyone else come across
this problem? -- mj

November 17, 2001
The following comments were received over the past few months. I am
posting them now.

Date: June 14, 2001
From: Pete Chamlis [chamlis-p@mail.tmh.org]

Regarding the issue of "false positive" troponin-I results obtained
from the Abbott AxSym...

There is a lot of discussion throughout the field of medical technology about
the need to re-evaluate the "cut-off" point for a positive troponin I.
It is pretty much common thought that the AxSym cut-off suggestion of 2.0 ng/ml
is certainly calling positive some patients who are not. Although, expensive,
the rapid bedside Cardiac Status test from Spectral labs seems to do a good job
of matching result to patient condition. We're re-evaluating our AxSym cutoff
point using the Spectral kit, along with chart and progress review.

Pete Chamlis,
Tallahassee, FL
chamlis-p@mail.tmh.org

Also, any comments that any pathologists or physicians out there might have
regarding updated Troponin T testing (on the Roche Elecsys) vs Troponin I would
be appreciated. Please feel free to privately email me, as well as posting to
the board.

Date: August 2, 2001
From: nabila.babar@cinhlthe.rcc.org

Responding to Bree Ann Borof's comments from Jan. 2000, I have faced similar
problems in at least three of my patients. One of them had elevated
creatinine of 2.4 but the other two did not. In both of these two, CPK's
were negative, history was atypical and repeat troponin was negative. So I
do not know what the real significance of troponin is.

Date: August 4, 2001
From: tjrahaim@mindspring.com

A 20% false positive is high but what is the false positive in mammo?

It's true that all tests have false positive and false negative
rates. But it is hard to compare these rates in settings that are so
different -- screening for malignancy and ruling out myocardial infarction in
the ER. The costs and consequences of false positives and false
negatives are very different and would need to be taken into account in any
comparison. --mj

Date: September 28, 2001
From: P. Smith, RN [biscuit54@hotmail.com]

In response to the request for more info regarding falsely elevated Troponins
I, have one case study that is baffling. It is a 28y female with elevated
Troponin I, negative CK-MB, negative EKG, negative history other than recent
history of atypical and reproducible chest pain. In addition, this patient had
normal renal function. Errors in performance and technique were ruled out. I am
currently searching for more information about falsely positive Troponins and
would be interested in any insight you can offer.

Sincerely, P. Smith, RN

Date: November 6, 2001
From: No valid return email address or name received

We have changed our
specimen requirement to green top tubes (na heparin) to eliminate false positive
due to fibrin clots. In cases where the green top is not available an extra spin
is done before assaying for troponin.Our methodology is the Axsym. lg

December 27, 2001
From: Olawale Ogunnuga MBChB [olawaleo@hotmail.com]

Causes of raised Troponin T/I include

Severe Renal Dsease
Pulmonary Emboli
Pericarditis
Cardiomyopathies

The last two causes probably due to concomitant mild cardiac damage. Ref.
JAMA, November 21, 2001-Vol 286, No 19

Olawale Ogunnuga MBChB

The reference in JAMA, particularly the editorial in this issue, gives a good
summary of some of the issues involved with Troponin testing. --mj